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IPIL

Cancer Type: Skin, Melanoma  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
New Drug Funding Program
    Ipilimumab - Previously Untreated Advanced Unresectable Melanoma
New Drug Funding Program
    Ipilimumab - Previously Treated Advanced Unresectable Melanoma
A - Regimen Name

IPIL Regimen
Ipilimumab


Disease Site
Skin - Melanoma

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

1. Treatment of previously untreated patients with advanced, unresectable melanoma who have an ECOG performance status of ≤ 1, are asymptomatic/stable if they have known brain metastases, and are not currently receiving immunosuppressive therapy.*

2. Treatment of advanced unresectable melanoma in patients who have an ECOG performance status ≤ 1 and who have received at least one systemic therapy for advanced melanoma.
OR
Re-induction after disease progression in patients with an ECOG performance status ≤ 1, who have had either complete or partial response or prolonged stable disease (at least three months duration) to prior ipilimumab.*

*See NDFP eligibility forms for detailed funding criteria.


Supplementary Public Funding

ipilimumab
New Drug Funding Program (Ipilimumab - Previously Untreated Advanced Unresectable Melanoma) (NDFP Website)

ipilimumab
New Drug Funding Program (Ipilimumab - Previously Treated Advanced Unresectable Melanoma) (NDFP Website)

 
B - Drug Regimen

ipilimumab
3 mg /kg IV over 90 minutes* Day 1

Each 5 mg (=1 mL) of drug contains 2.3 mg (0.1 mmol) of sodium. The sodium content should be taken into consideration in patients on a controlled sodium diet.

*Evidence from clinical trials suggests a 30 minute infusion time may be used safely (Momtaz 2015).

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C - Cycle Frequency

REPEAT EVERY 21 DAYS

Up to a total of 4 cycles, unless disease progression or unacceptable toxicity occurs

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal

Other Supportive Care:

  • Consider pre-medication and post-infusion treatment with acetaminophen.
  • For ipilimumab-related drug fever, premedicate with acetaminophen for subsequent doses and may repeat the antipyretic at 6-12 hours after the ipilimumab infusion.
  • Consider premedication with diphenhydramine with prior hypersensitivity reactions; avoid steroids as they may abrogate activity
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Each 5 mg (=1 mL) of drug contains 2.3 mg (0.1 mmol) of sodium. The sodium content should be taken into consideration in patients on a controlled sodium diet. If pituitary imaging or endocrine function tests are abnormal, withhold treatment.

Dosage with toxicity

There are no dose reductions for ipilimumab.  Doses are either delayed or discontinued with toxicity. The following recommendations are from the product monograph or consensus recommendations. 

Toxicity

Hold?

Management

Next dose

Grade 2 dermatitis or pruritus

No

Treat symptomatically (includes topical steroids); if no improvement in 7 days consider PO prednisone 0.5-1 mg/kg/day*. 

N/A

Grade 3 dermatitis or pruritus Yes Treat symptomatically; consider oral antibiotics. Start PO prednisone 0.5-1 mg/kg/day*.  Hold until recovers to ≤ grade 1; consider discontinuation if no improvement within 12 weeks. 

Ocular effects (any grade episcleritis, iritis, uveitis)

No

Treat with topical steroids.  

Discontinue if no response to topical therapy.

Grade 2 diarrhea/colitis

Yes

Treat symptomatically (includes loperamide). Consider starting steroids right away or after 24 hrs of loperamide.

Give prednisone 0.5-1 mg/kg/day*.

May retreat if recovers to ≤ grade 1 and on <7.5 mg prednisone/day.

Grade 2 hepatitis  Yes Recheck liver function in 2-3 days & if no improvement, start prednisone 0.5-1 mg/kg/day*

Other  grade 2 immune toxicity, including symptomatic endocrinopathy and neurotoxicity

Yes

Give prednisone 1-2 mg/kg/day*.

Start endocrine replacement therapy as indicated.

Severe immune-mediated:

  • grade 3-4 colitis/diarrhea
  • grade 3-4 hepatitis
  • grade 3-4 neurologic (motor or sensory neuropathy, including myasthenia and GBS
  • grade 4 dermatitis (including TEN and SJS, full thickness dermal ulceration, necrotic, bullous or hemorrhagic manifestations)
  • grade 3-4 nephritis
  • Non-infectious myocarditis
  • grade 3-4 other organ

 

Discontinue. Give high dose steroids* (prednisone 1-2 mg/kg/d) ± additional immunosuppression: Infliximab for enterocolitis or mycophenolate for hepatitis/other toxicity.

 

Discontinue

Inability to complete treatment within 16 weeks of the first dose because of toxicity.

Persistent moderate or clinically significant adverse reactions or inability to reduce corticosteroid dose to prednisone 7.5 mg/day or equivalent.

 

Discontinue

Discontinue

 *Taper steroids over ≥ 1 month once recovers to ≤ grade 1

Infusion-related reactions:

Toxicity grade Action
Mild (e.g. localized rash, mild pruritus, flushing)
  • ↓ infusion rate until recovery and monitor patient; then complete infusion at original planned rate if tolerated.
  • Diphenhydramine 50mg IV may be given if needed.  May consider premedication for subsequent doses.
Moderate (e.g. generalized pruritus, flushing, rash, dyspnea,
hypotension with systolic BP >80 mmHg)
  • Interrupt infusion and give diphenhydramine 50mg IV; monitor patient closely.  
  • If resuming infusion, ↓ rate to 50% and may increase to initial rate if tolerated. 
  • Corticosteroids may decrease any beneficial immunologic effect, but may be given at physician's discretion.
  • If reaction recurs after restarting infusion, stop the infusion and do not give any further ipilimumab on that day. 
  • Consider premedications (diphenhydramine, acetaminophen) for subsequent doses and follow infusion rate as above.
Severe (e.g. bronchospasm, generalized urticaria, SBP <80 mm Hg, or angioedema)
  • Discontinue ipilimumab permanently; monitor patient closely.
  • Consider bronchodilators, epinephrine, diphenhydramine, corticosteroids as needed.



Hepatic Impairment

Safety and efficacy have not been studied in patients with hepatic impairment. See table above for dose modifications for drug induced hepatic toxicity. Population pharmacokinetic data suggest the following for hepatic impairment:

Impairment
LFTs
Ipilimumab dose
Mild
Bilirubin 1-1.5 x ULN or AST > ULN
No change
Moderate
Bilirubin > 1.5 to 3 x ULN
Caution; no data
Severe
Bilirubin > 3 x ULN
Caution; no data

Renal Impairment

Safety and efficacy have not been studied in patients with renal impairment. Pharmacokinetic data suggest no dosage adjustment is necessary in patients with mild to moderate renal impairment. No data are available for severe renal impairment.


Dosage in the Elderly

No dose adjustment required. No differences in efficacy or safety were reported in those ≥ age 65.

 

 


 
F - Adverse Effects

Refer to ipilimumab drug monograph(s) for additional details of adverse effects

 

 


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

 

  • Diarrhea (may be severe colitis)
  • Rash, pruritus (may be severe)
  • Fatigue
  • Nausea, vomiting
  • Anorexia, weight loss
  • Abdominal pain

 

  • Increased LFTs
  • Infection (atypical)
  • Adrenal insufficiency
  • Cushingoid
  • Hypopituitarism
  • Hyper/hypothyroidism
  • Nephrotoxicity
  • Uveitis, episcleritis
  • Optic neuritis
  • GI perforation, hemorrhage
  • Hypersensitivity
  • Neuropathy
  • Pneumonitis
  • Arteritis
  • Arrhythmia
  • Cardiotoxicity
  • DRESS
  • Guillain-Barre syndrome
  • Myasthenia gravis
  • Hemolysis
  • Pancreatitis
  • Polymyositis
  • Encephalitis/meningoencephalitis
  • Myocarditis
 
G - Interactions

Refer to ipilimumab drug monograph(s) for additional details


  • Ipilimumab is not expected to have pharmacokinetic drug-drug interactions, since it is not metabolized by CYP450 or other drug metabolizing enzymes.
  • In a drug interaction study, ipilimumab did not affect the pharmacokinetics of CYP1A2, CYP2E1, CYP2C8 and CYP3A4 substrates.
  • Systemic immunosuppressants should be avoided before starting ipilimumab. Corticosteroids may be used to treat immune reactions.
  • Anticoagulants may increase the risk of GI hemorrhage; monitor patients closely if used together.
 
H - Drug Administration and Special Precautions

Refer to ipilimumab drug monograph(s) for additional details


Administration:

  • Do not administer as an IV push or bolus injection.
  • Infuse as an IV infusion over 90 minutes, with a compatible low protein binding in-line filter. (Evidence from clinical trials suggests a 30 minute infusion time may be used safely, Momtaz 2015).
  • A separate infusion line must be used for infusing ipilimumab.
  • Must flush line with NS or D5W at the end of the infusion.
  • Allow the vials to stand at room temperature for 5 minutes before withdrawing the drug to a compatible container.
  • Ipilimumab may be administered without dilution after transferring to a compatible container.
  • It may also be diluted in NS or D5W to a concentration between 1mg/mL to 4mg/mL.
  • Do not shake the solution.
  • Solution may contain translucent-to-white amorphous particles.
  • Compatible with glass, PVC and non-PVC bags
  • Compatible with PVC IV extension or administration sets, polyethersulfone (0.2 and 1.2 micron) and nylon (0.2 micron) in-line filters.
  • Infusion solution (undiluted or diluted) may be stored for up to 24 hours refrigerated or at room temperature. 
  • Refrigerate original vials (2 to 8°C) and protect them from light. Do not freeze.

Contraindications:

  • Patients who are hypersensitive to ipilimumab or any of its components
  • Patients with active, life-threatening autoimmune disease, or with organ transplantation graft where further immune activation is potentially imminently life-threatening
  • Concurrent use of ipilimumab and vemurafenib is not recommended as severe LFT increases have been reported in clinical trials.

Other Warnings/Precautions:

  • Ipilimumab may cause severe and fatal immune-related reactions, which may affect multiple organ systems including GI, hepatic, skin, nervous, endocrine or others.  Close monitoring, prompt diagnosis and appropriate management are essential to minimize life-threatening complications.
  • Caution in patients who have previously experienced severe or life-threatening skin reactions to prior cancer immune-stimulating therapy
  • Usage in patients with ocular melanoma or central nervous metastases has not been studied.
  • Patients on anticoagulants are at increased risk of bleeding.

Pregnancy and lactation:

  • IgG1 is known to cross the placental barrier and may cause harm to the developing fetus. Effects are likely to be greater in the second and third trimesters Ipilimumab is not recommended for use in pregnancy; effective contraception should be used by both sexes during treatment, and for at least 3 months after the last dose.
  • Breastfeeding should be avoided.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • Electrolytes; Baseline and before each dose
  • Liver function tests; Baseline and before each dose
  • Monitor patients on anticoagulants carefully; Baseline and as clinically indicated
  • Thyroid function tests; Baseline and before each dose
  • Clinical toxicity assessment for immune-related reactions, including diarrhea, GI perforation, hypophysitis, adrenal insufficiency, other endocrinopathies, hepatic, pulmonary, ocular, skin or neurologic effects and fatigue; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
2 hours
Pharmacy Workload (average time per visit)
17.795 minutes
Nursing Workload (average time per visit)
42.417 minutes
 
K - References

Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.

Ipilimumab drug monograph, Cancer Care Ontario.

November 2017 updated dose modifications, adverse effects and pregnancy sections


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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